Synthesis and biological evaluation of anti-1-amino-2-[18F]fluoro-cyclobutyl-1-carboxylic acid (anti-2-[18F]FACBC) in rat 9L gliosarcoma

Article abstract of DOI:10.1016/j.bmcl.2010.02.048

A new [¹⁸F] labeled amino acid anti-1-amino-2-[¹⁸F]fluoro-cyclobutyl-1-carboxylic acid 9 (anti-2-[¹⁸F]FACBC) was synthesized in 30% decay-corrected yield with high radiochemical purity over 99%. The cyclic sulfamidate precursor was very stable and highly reactive towards nucleophilic radiofluorination. Cell uptake assays with rat 9L gliosarcoma cells showed that [¹⁸F]9 was transported into tumor cells via multiple amino acid transport systems, including L and A systems. Biodistribution study in rats with intracranial 9L gliosarcoma tumors demonstrated that [¹⁸F]9 had a rapid and prolonged accumulation in tumors with 26:1 tumor to brain ratio at 120 min post-injection. In this model, [¹⁸F]9 is a potential PET tracer for brain tumor imaging.

Full text of DOI:10.1016/j.bmcl.2010.02.048

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2140–2143
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
18
Synthesis and biological evaluation of anti-1-amino-2-[ F]fluoro-cyclobutyl-
1
8
1
-carboxylic acid (anti-2-[ F]FACBC) in rat 9L gliosarcoma
a
a
a
b
a,*
Weiping Yu , Larry Williams , Vernon M. Camp , Jeffrey J. Olson , Mark M. Goodman
a
Department of Radiology, School of Medicine, Emory University, Atlanta, GA 30322, USA
Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA
b
a r t i c l e i n f o
a b s t r a c t
A new [18F] labeled amino acid anti-1-amino-2-[18F]fluoro-cyclobutyl-1-carboxylic acid 9 (anti-2-
Article history:
Received 29 December 2009
Revised 9 February 2010
Accepted 10 February 2010
Available online 14 February 2010
18
[
F]FACBC) was synthesized in 30% decay-corrected yield with high radiochemical purity over 99%.
The cyclic sulfamidate precursor was very stable and highly reactive towards nucleophilic radiofluorina-
18
tion. Cell uptake assays with rat 9L gliosarcoma cells showed that [ F]9 was transported into tumor cells
via multiple amino acid transport systems, including L and A systems. Biodistribution study in rats with
1
8
intracranial 9L gliosarcoma tumors demonstrated that [ F]9 had a rapid and prolonged accumulation in
Keywords:
Fluorine-18
Amino acids
Non-natural
Brain tumors
PET
18
tumors with 26:1 tumor to brain ratio at 120 min post-injection. In this model, [ F]9 is a potential PET
tracer for brain tumor imaging.
Ó 2010 Elsevier Ltd. All rights reserved.
Radiolabeled amino acids, representing a class of metabolically
based radiotracers, have been of interest for scientists to study po-
analogue 2-[18F]fluoro-2-deoxyglucose ([18F]FDG), which is the
only PET agent currently used for clinical oncology, as FDG has
some limitations including high uptake in inflammatory tissue
and normal gray matter of the brain. In contrast, non-natural ami-
tential imaging characteristics with positron emission tomography
–16
(
PET) and single photon emission tomography (SPECT).1
Amino
1
8
acids are important biological substrates in virtually all biological
process and are required nutrients for proliferating tumor
no acids such as anti-1-amino-3-[ F]fluorocyclobutane-1-carbox-
1
8
lic acid (anti-[ F]FACBC), has demonstrated lower uptake in the
6
,10,17
cells.
Many tumor cells demonstrate increased amino acid
inflamed popliteal lymph nodes and benign prostatic hyperplasia
18,19
18
28
transport relative to normal tissues.
than those for [ F]FDG in a rat prostate cancer model.
1
8
Amino acids used for tumor imaging can be divided into two
major categories, naturally occurring amino acids and their struc-
turally similar analogues, and non-natural amino acids. Non-natu-
ral amino acids generally have greater metabolic stability and can
be labeled with longer-lived radionuclides such as fluorine-18 for
PET imaging. Amino acids enter normal and neoplastic cells pri-
marily through specific membrane associated carrier proteins with
varying selectivity based on their chemical structure. For radiola-
beled amino acids, tumor uptake is primarily determined by amino
acid transport rather than protein synthesis.6 The most abundant
A number of [ F] labeled non-natural cyclobutyl amino acids
have been prepared in our lab, including anti- and syn-1-amino-3-
1
8
18
29,30
[
F]fluorocyclobutane-1-carboxylic acid (anti-[ F]FACBC
and
1
8
31
18
syn-[ F]FACBC ) and syn- and anti-1-amino-3-[ F]fluoromethyl-
cyclobutane-1-carboxylic acid (syn- and anti-[ F]FMACBC). These
1
8
32
compounds showed high tumor uptake in 9L rat gliosarcoma tu-
1
8
mors. Among these amino acids, the PET tracer anti-[ F]FACBC is
undergoing initial human clinical trials to validate it as a valuable
imaging agent for the diagnosis and management of treatment of
,10
33–35
cancer.
In an effort to develop more radiotracers for PET tumor
amino acid transport systems in most mammalian cells are system
imaging, we report herein the synthesis, radiolabeling and biological
A, system L, system ASC, and system Gly.1
0,20–25
All of these trans-
port systems are sodium-dependent except system L. Amino acid
transport is upregulated in many tumor types. Certain amino acid
evaluation of anti-1-amino-2-[ F]fluorocyclobutane-1-carboxylic
18
1
8
acid (anti-2-[ F]FACBC, 9) with a rat 9L gliosarcoma cell line and
1
8
in Fischer rats with intracranial 9L tumors. anti-2-[ F]FACBC is a
1
8
transporters also are involved in cell signaling and may play
constitutional isomer of anti-[ F]FACBC, also known as anti-3-
important roles in tumor biology.2
2,26,27
Additionally, the amino
[ F]FACBC(Fig. 1). Onthebasisof theobservationandthepromising
18
1
8
acids developed for tumor imaging may complement the glucose
results obtained with anti- and syn-[ F]FACBC and their analogues
1
8
anti- and syn-[ F]FMACBC, our goal was to expend the synthetic
scope to study the effect of structure of cyclobutyl amino acids on
the biological properties of these compounds.
*
Corresponding author.
E-mail address: mgoodma@emory.edu (M.M. Goodman).
0
960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.048

W. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2140–2143
2141
of [18F]9 was not determined directly, the maximum amount of
unlabeled material in the final product arising from the precursor
is about 1 mg in each case. On the basis of 100 mCi yield at EOS,
the amount of nonradioactive material in the final dose is approx-
HOOC
NH2
HOOC
NH2
F
F
imately 10
lg per mCi. This amount is comparable to the amount
anti-FACBC
syn-FACBC
18
of nonradioactive material present in doses of [ F]FDG and anti-
1
8
29,40
[
F]FACBC which arises from the triflate precursors.
On the
basis of the average dosage of 5–20
l
Ci of [18F]9 per animal in
the in vivo study, the maximum amount of unlabeled material aris-
ing from the precursor associated with [ F]9 per injection was
HOOC
NH2
HOOC
NH2
18
F
F
approximately 0.05–0.2 lg. The major byproduct arising from the
labeling precursor is expected to consist of anti-1-amino-2-hydro-
xy-cyclobutyl-1-carboxylic acid arising from competing nucleo-
philic reaction at C-2 by water or hydroxide ions.
syn-2-FACBC
anti-2-FACBC 9
Figure 1. Structures of FACBC and 2-FACBC.
The non-radioactive anti-2-FACBC 9 was prepared from the syn-
alcohol 5, which was reacted with (diethylamino)sulfur trifluoride
4
1,42
(
(
DAST)
followed by acid hydrolysis using trifluoroacetic acid
The 2-FACBC cyclic sulfamidate precursor for fluorine-18 radio-
labeling was prepared in a series of synthetic steps starting from
,2-bis(trimethylsiloxy)cyclobtene (1), which is shown in Scheme
TFA) as shown in Scheme 3.
The in vitro studies were performed in 9L rat gliosarcoma cells
1
1
in Hank’s Balanced Salt Solution (HBSS) incubated for 30 min at
7 °C with or without inhibitors to evaluate the compound tumor
. The compound 1,2-bis(trimethylsiloxy)cyclobtene was treated
3
36
with benzyl alcohol in an acidic media to afford 2-(benzyl-
oxy)cyclobutanone (2) in 62% yield. The hydantoins (3) were pre-
pared through modified Strecker synthesis in a 9:1 mixture of
syn- to anti-isomers as determined by 1H NMR. This mixture 3
was hydrolyzed in aqueous base solution to give syn- and anti-2-
benzyloxy-cyclobutane amino acids followed by the protection of
amino and carboxylic groups in the forms of N-Boc and tert-butyl
ester to afford syn- and anti-tert-butyl 2-(benzyloxy)-1-(tert-but-
oxycarbonylamino)cyclobutanecarboxylates (4) in 35% yield from
cell uptake profile and transport mechanism. 10 mM of 2-amino-
bicyclo[2.2.1]-heptane-2-carboxylic acid (BCH), 10 mM of N-
methyl-a-aminoisobutyric acid (MeAIB) and the combination of
1
0 mM of alanine-cysteine-serine (ACS, 3.3 mM of each amino
acid) were used as system L, system A, and system ASC amino acid
transport inhibitors, respectively. The results of the amino acid up-
take assays are depicted in Figure 2. In the absence of inhibitors,
18
anti-2-[ F]FACBC 9 showed good level of intracellular accumula-
tion, 3.3 ± 0.1% of the initial dose per 0.5 million cells (%ID/
2
. Catalytic debenzylation using palladium on active carbon re-
leased syn- and anti-alcohols (5) in quantitative yield. In the key
synthetic step, reaction of 5 with thionyl chloride in polar solvent
acetonitrile gave exclusive syn-isomer of cyclic sulfamidite (6) in
0% yield. The oxidation of 6 with sodium periodate provided syn-
5
5
 10 cells) in 9L gliosarcoma cells. ACS inhibited 73% of the up-
take compared to control (p <0.0001, one-way ANOVA). In the
presence of BCH, 59% of inhibition was observed compared to con-
trol (p = 0.0001, one-way ANOVA). Interestingly, 33% uptake inhi-
bition occurred with MeAIB relative to control (p = 0.0012, one-
way ANOVA). These results demonstrate that compound 9 enter
3
7
8
1
8
isomer of cyclic sulfamidate (7) in 96% yield as anti-2-[ F]FACBC
labeling precursor.
9
L gliosarcoma cells in vitro involves both system L and non-sys-
Radiofluorinated anti-2-[18F]FACBC 9 was prepared using no-
tem L transport, likely system A.
18
carrier-added (NCA) cyclotron-produced [ F]fluoride and K222 fol-
lowed by hydrolysis with 4 N hydrochloric acid.38 anti-2-[ F]FAC-
BC 9 was obtained by ion-retardation resin chromatographic
The in vivo biodistribution studies were performed in male
Fischer 344 rats with 9L tumors implanted intracranially. The
radioactivity in tumors and in normal tissues of tumor-bearing rats
18
3
1,39
purification
mately 85 min with decay-corrected yields (DCY) of 29.5 ± 5.4%
n = 5) with radiochemical purity over 99% as measured by radio-
(Scheme 2). The procedure required approxi-
(n = 4 each time point) was calculated at 15, 30, 60, and 120 min
post-injection (pi) and normalized as percent injected dose per
(
18
gram tissue (%ID/g). The uptake of radioactivity of anti-2-[ F]FAC-
metric TLC. In a representative synthesis, a total of 103 mCi of
F]9 at end of synthesis (EOS) was obtained from 445 mCi of
F]fluoride at end of bombardment (EOB) using 1 mg (3 mol)
BC 9 in tumor and brain is presented in Figure 3. The experiments
showed that this amino acid had rapid and prolonged accumula-
tion in tumors, in the values of 0.51, 0.66, 0.65, and 0.60%ID/g at
1
1
8
8
[
[
l
of cyclic sulfamidate precursor syn-7. While the specific activity
1
5, 30, 60, and 120 min pi, respectively, and was significantly high-
H
O
N
OTMS
O
t-BuO C NHBoc
2
a
b
c, d, e
O
NH
OBn
OBn
OBn
OTMS
1
2
3, syn : anti = 90 : 10
4
Boc
Boc
O
t-BuO C NHBoc
2
O
f
g
t-BuO C
2
N
h
t-BuO C
2
N
S
S
O
OH
O
O
5
6, syn
7, syn
Scheme 1. Synthesis of anti-2-[18F]FACBC cyclic sulfamidate precursor 7. Reagents and conditions: (a) BnOH, HCl, Et
c) NaOH (aq), 120 °C; (d) (Boc) O, Et N, CH OH, rt; (e) Cl CC(–NH)OC(CH , rt; (f) H , Pd–C (cat.), rt; (g) SOCl , pyridine, CH
°C to rt.
O, 0–80 °C; (b) (NH
CN, À40 °C; (h) NaIO4, RuCl
)
CO
, NH
Cl, KCN, EtOH/H
O, 70 °C;
2
4
2
3
4
2
(
0
2
3
3
3
)
3 3
2
2
3
3
(cat.), CH
3
CN, H
2
O,

2
142
W. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2140–2143
O
S
Boc
N CO t-Bu
Boc
O
O
-O
H N CO H
2 2
N
CO t-Bu
2
2
S
a
b
O
1
8
18F
O
F
7, syn
8, anti
9, anti
Scheme 2. Radiosynthesis of anti-2-[18F]FACBC 9. Reagents and conditions: (a) [18F]KF, K222, 90 °C, 10 min; (b) 4 N HCl, 110 °C, 10 min.
t-BuO C NHBoc
t-BuO C NHBoc
HO C NH2
2
2
2
a
b
OH
F
F
5
10
9
Scheme 3. Synthesis of anti-2-FACBC 9. Reagents and conditions: (a) DAST, DCM, À70 °C to rt, overnight; (b) TFA, DCM, rt.
4
Cell Uptake and Inhibition Assys
3
2
1
0
.5
3
.5
2
control
BCH
MeAIB
ACS
.5
1
.5
0
anti-2-FACBC
Figure 2. 9L Cell uptake and inhibition assays with [18F]9. Uptake is normalized as the initial dose per 0.5 million cells (%ID/5 Â 10 cells). Error bars indicate ±standard
5
deviation (n = 3). Ã = 59% reduction versus control, p = 0.0001. ÃÃ = 33% reduction versus control, p = 0.0012. ÃÃÃ = 73% reduction versus control, p <0.0001.
[18
study. The tumor to brain ratios of [ F] labeled anti-FACBC
F]fluoride was not generated during the time course of the
anti-2-FACBC Uptake in Tumor and Brain
1
8
30
,
1
.9
.8
.7
.6
.5
.4
.3
.2
.1
0
3
1
32
32
tumor
brain
syn-FACBC syn-FMACBC and anti-FMACBC at 60 min pi were
.6:1, 7.6:1, 6.9:1, and 8.9:1, respectively, in the same animal mod-
0
0
0
0
0
0
0
0
0
6
el. Thus, the candidate compound 9 is comparable with anti/syn-
FACBC and anti/syn-FMACBC for the good tumor to brain ratios.
The remarkable difference of this amino acid compared with its
1
8
analogues FACBC and FMACBC was that anti-2-[ F]FACBC 9 en-
tered 9L tumors through certain degree of non-system L amino
acid transport, possibly system A transport, as demonstrated in cell
inhibition study. One of representative system A substrates is ami-
13,37
no acid 2-amino-3-fluoro-2-methylpropanoic acid (FAMP).
Amino acids 2-FACBC 9 and FAMP possess amazing similar struc-
tures as shown in Figure 4. It may not be surprised that these
two compounds share similar in vitro and in vivo properties since
the chemical structure of a compound is a major factor to regulate
the selectivity of the transport systems. The system A transport is
inactive at the luminal surface of normal endothelium of the
1
5 min
30 min
60 min
120 min
Figure 3. Radioactivity uptake in tumor and brain of 9L tumor-bearing Fisher rats
with anti-2-[18F]FACBC 9. Uptake is normalized as percent injected dose per gram
tissue (%ID/g). Error bars indicate ±standard deviation (n = 4 at each time point). p
<
0.0001 (at all time points, tumor vs brain, one-way ANOVA).
er than in normal brain tissue (p <0.0001 at all time points, one-
way ANOVA). The uptake in normal brain tissue was less than
HO C NH2
HO C NH2
HO C NH2
2
2
2
0
.04%ID/g at all time points thus the tumor to normal brain uptake
F
F
F
ratios were 12:1, 17:1, 14:1, and 26:1 at 15, 30, 60, and 120 min pi,
1
8
respectively, for anti-2-[ F]FACBC 9. Low uptake was found in
blood, heart, liver, lung, muscle, and bone. The low bone uptake
with this radiotracer indicates that [18F]9 was stable and free
2
-FACBC 9
FAMP
Figure 4. The chemical structures of 2-FACBC 9 and FAMP.

W. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2140–2143
2143
1
3
blood–brain barrier (BBB), which might explain very low normal
13. McConathy, J.; Martarello, L.; Malveaux, E. J.; Camp, V. M.; Simpson, N. E.;
18
Simpson, C. P.; Bowers, G. D.; Olson, J. J.; Goodman, M. M. J. Med. Chem. 2002,
brain uptake of anti-2-[ F]FACBC 9. The higher tumor to brain ra-
tio of compound [ F]9 compared to anti- and syn-[ F]FACBC and
anti- and syn-[ F]FMACBC was contributed to the lower normal
brain uptake.
In summary, a new non-natural cyclobutyl amino acid, anti-2-
F]FACBC 9 has been synthesized and biologically evaluated. This
compound demonstrated moderate levels of tumor uptake in vitro
and in vivo in a 9L rat gliosarcoma brain tumor model and it is an
amino acid transporter substrate. These results are comparable
with those of anti- and syn-FACBC and anti- and syn-FMACBC in
the same animal model, which support the candidacy of anti-2-
4
5, 2240.
1
8
18
1
4. McConathy, J.; Martarello, L.; Malveaux, E. J.; Camp, V. M.; Simpson, N. E.;
Simpson, C. P.; Bowers, G. D.; Zhang, Z.; Olson, J. J.; Goodman, M. M. Nucl. Med.
Biol. 2003, 30, 477.
1
8
15. Sutinen, E.; Jyrkkio, S.; Gronroos, T.; Haaparanta, M.; Lehikoinen, P.; Nagren, K.
Eur. J. Nucl. Med. 2001, 28, 847.
[18
16. Wester, H. J.; Herz, M.; Weber, W.; Heiss, P.; Senekowitsch-Schmidtke, R.;
Schwaiger, M.; Stocklin, G. J. Nucl. Med. 1999, 40, 205.
1
7. Grosu, A. L.; Weber, W. A.; Franz, M.; Staerk, S.; Piert, M.; Thamm, R.;
Gumprecht, H.; Schwaiger, M.; Molls, M.; Nieder, C. Int. J. Radiat. Oncol. Biol.
Phys. 2005, 63, 511.
1
1
2
8. Jager, P. L. J. Nucl. Med 2002, 43, 1207.
9. McConathy, J.; Goodman, M. M. Cancer Metastasis Rev. 2008, 27, 555.
0. Christensen, H. N. Physiol. Rev. 1990, 70, 43.
1
8
[
F]FACBC 9 as a promising PET brain tumor imaging agent.
21. Souba, W. W.; Pacitti, A. J. J. Parenter. Enteral Nutr., JPEN 1992, 16, 569.
2
2
2
2
2. Johnstone, R. M.; Scholefield, P. G. Adv. Cancer Res. 1965, 9, 143.
3. Palacin, M.; Estevez, R.; Bertran, J.; Zorzano, A. Physiol. Rev. 1998, 78, 969.
4. Saier, M. H. J.; Daniels, G. A.; Boerner, P.; Lin, J. J. Membr. Biol. 1988, 104, 1.
5. Shotwell, M. A.; Kilberg, M. S.; Oxender, D. L. Biochim. Biophys. Acta, Rev.
Biomembr. 1983, 737, 267.
Acknowledgments
We are grateful to Dr. Bing Wang of the NMR Center at Emory
University for his assistance with NMR studies, Zhaobin Zhang
and Eugene Malveaux for the assistance with the in vivo studies.
Research supported by Georgia Research Alliance and Georgia Can-
cer Coalition.
26. Fuchs, B. C.; Bode, B. P. Semin. Cancer Biol. 2005, 15, 254.
2
7. Fuchs, B. C.; Finger, R. E.; Onan, M. C.; Bode, B. P. Am. J. Physiol. Cell Physiol. 2007,
2
93, C55.
28. Oka, S.; Hattori, R.; Kurosaki, F.; Toyama, M.; Williams, L. A.; Yu, W.; Votaw, J.
R.; Yoshida, Y.; Goodman, M. M.; Ito, O. J. Nucl. Med. 2007, 48, 46.
9. McConathy, J.; Voll, R. J.; Yu, W.; Crowe, R. J.; Goodman, M. M. Appl. Radiat. Isot.
2
2003, 58, 657.
References and notes
30. Shoup, T. M.; Olson, J.; Hoffman, J. M.; Votaw, J.; Eshima, D.; Eshima, L.; Camp,
V. M.; Stabin, M.; Votaw, D.; Goodman, M. M. J. Nucl. Med. 1999, 40, 331.
3
3
1. Yu, W.; Williams, L.; Camp, V. M.; Malveaux, E.; Olson, J. J.; Goodman, M. M.
Bioorg. Med. Chem. 2009, 17, 1982.
2. Martarello, L.; McConathy, J.; Camp, V. M.; Malveaux, E. J.; Simpson, N. E.;
1
2
3
4
5
6
7
8
9
.
.
.
.
.
.
.
.
.
Biersack, H. J.; Coenen, H. H.; Stocklin, G.; Reichmann, K.; Bockisch, A.; Oehr, P.;
Kashab, M.; Rollmann, O. J. Nucl. Med. 1989, 30, 110.
Daemen, B. J. G.; Elsinga, P. H.; Paans, A. M.; Lemstra, W.; Konings, A. W.;
Vaalburg, W. Nucl. Med. Biol. 1991, 18, 503.
Dunzendorfer, U.; Schmall, B.; Bigler, R. E.; Zanzonico, P. B.; Conti, P. S.; Dahl, J.
R.; Kleinert, E.; Whitmore, W. F. Eur. J. Nucl. Med. 1981, 6, 535.
Hatazawa, J.; Ishiwata, K.; Itoh, M.; Kameyama, M.; Kubota, K.; Ido, T.;
Matsuzawa, T.; Yoshimoto, T.; Watanuki, S.; Seo, S. J. Nucl. Med. 1990, 30, 1809.
Ishiwata, K.; Hatazawa, J.; Kubota, K.; Kameyama, M.; Itoh, M.; Matsuzawa, T.;
Takahashi, T.; Iwata, R.; Ido, T. Eur. J. Nucl. Med. 1989, 15, 665.
Jager, P. L.; Vaalburg, W.; Pruim, J.; de Vries, E. G.; Langen, K. J.; Piers, D. A. J.
Nucl. Med. 2001, 42, 432.
Kubota, K.; Ishiwata, K.; Kubota, R.; Yamada, S.; Takahashi, J.; Abe, J.; Fukuda,
H.; Ido, T. J. Nucl. Med. 1996, 37, 320.
Langen, K. J.; Hamacher, K.; Weckesser, M.; Floeth, F.; Stoffels, G.; Bauer, D.;
Coenen, H. H.; Pauleit, D. Nucl. Med. Biol. 2006, 33, 287.
Langstrom, B.; Antoni, G.; Gullberg, P.; Halldin, C.; Malmborg, P.; Nagren, K.;
Rimland, A.; Svard, H. J. Nucl. Med. 1987, 28, 1037.
Simpson, C. P.; Olson, J. J.; Bowers, G. D.; Goodman, M. M. J. Med. Chem. 2002,
4
5, 2250.
3
3
3
3. Nye, J. A.; Schuster, D. M.; Yu, W.; Camp, V. M.; Goodman, M. M.; Votaw, J. R. J.
Nucl. Med. 2007, 48, 1017.
4. Schuster, D. M.; Votaw, J. R.; Nieh, P. T.; Yu, W.; Nye, J. A.; Master, V.; Bowman,
F. D.; Issa, M. M.; Goodman, M. M. J. Nucl. Med. 2007, 48, 56.
5. Schuster, D. M.; Nye, J. A.; Nieh, P. T.; Votaw, J. R.; Halkar, R. K.; Issa, M. M.; Yu,
W.; Sepulveda, J.; Zeng, W.; Young, A.; Goodman, M. M. Mol. Imaging Biol. 2009,
1
1, 434.
3
3
6. Bisel, P.; Breitling, E.; Frahm, A. W. Eur. J. Org. Chem. 1998, 4, 729.
7. Yu, W.; McConathy, J.; Williams, L.; Camp, V. M.; Malveaux, E. J.; Zhang, Z.;
Olson, J. J.; Goodman, M. M. J. Med. Chem. 2010, 53, 876.
3
3
4
8. Yu, W.; Williams, L.; Malveaux, E.; Camp, V. M.; Olson, J. J.; Goodman, M. M.
Bioorg. Med. Chem. Lett. 2008, 18, 1264.
9. Yu, W.; McConathy, J.; Olson, J. J.; Camp, V. M.; Goodman, M. M. J. Med. Chem.
2007, 50, 6718.
1
1
1
0. Laverman, P.; Boerman, O. C.; Corstens, F. H.; Oyen, W. J. Eur. J. Nucl. Med. 2002,
0. Alexoff, D. L.; Casati, R.; Fowler, J. S.; Wolf, A. P.; Shea, C.; Schlyer, D. J.; Shiue, C.
Y. Int. J. Rad. Appl. Instrum. Part A 1992, 43, 1313.
1. Ferreira, S. B. Synlett 2006, 7, 1130.
2. Golubev, A. S.; Schedel, H.; Radics, G.; Fioroni, M.; Thusta, S.; Burger, K.
Tetrahedron Lett. 2004, 45, 1445.
29, 681.
1. Lilja, A.; Bergstrom, K.; Hartvig, P.; Spannare, B.; Halldin, C.; Lundqvist, H.;
Langstrom, B. Am. J. Neuroradiol. 1985, 6, 505.
2. Luurtsema, G.; Medema, J.; Elsinga, P. H.; Visser, G. M.; Vaalburg, W. Appl.
Radiat. Isot. 1994, 45, 821.
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